Glikopeptid-glycyrrhizic acid dimethyl ester, l-aspartic acid, exhibiting anti-aids activity

 

(57) Abstract:

Usage: as an anti-AIDS funds. Entity: product: 3-0-[2-0-(N - b-D-glucopyranosyloxy-L-aspartic acid dimethyl ester)-N - b-D-glyukopiranozil uranyl-L-aspartic acid dimethyl ester] -(3 b, 20 b )-11,30-dioxo-30-(N-L-aspartic acid dimethyl ester)-30-norolean-12-ene. Output 76,0% . []2D0= +60(C = 0.02 methanol) BF C60H89N3O25. Reagent 1: -glycyrrhizin acid. Reagent 2: dimethyl ester of L-aspartic acid. Conditions: in a medium dry dioxane in the presence of N-hydroxysuccinimide and N,N'-dicyclohexylcarbodiimide, followed by the addition of triethylamine. table 1.

The invention relates to new chemical compound, specifically to glycopeptide-glycyrrhizic acid dimethyl ester, L-aspartic acid: 3,0-[2-0-(N- -D-glyukopiranozil - uranyl-L-aspartic acid dimethyl ester)-N-D-glyukopiranozil uranyl-L-aspartic acid dimethyl ester] - (3 , 20 )-11,30-dioxo-30-(N-L-aspartic acid dimethyl ester)-30-norolean-12-ene of the formula I

where I R - L - Asp (OMe)2;

II R - OH manifesting anti-AIDS activity.

The specified connection and its swayoco treatments for AIDS. Identified a number of compounds inhibiting the replication of human immunodeficiency virus (HIV) in vitro: ribavirin, posteromarginal acid, azidothymidine (AZT), 2,3-dideoxynucleoside etc. Initiated clinical use of a number of compounds, but the results are not yet fully interpreted [1, 2].

-Glycyrrhizin acid - the active principle of licorice root extract. In recent years it was discovered near Japanese scientists that glycyrrhizin acid is an effective inhibitor of HIV replication, at the same time acts as an immunostimulant [1-4]. Therefore, glycyrrhizin acid is an effective therapeutic agent for the treatment of AIDS. However, glycyrrhizin acid is ineffective as an inhibitor of HIV replication in chronically infected cells.

The aim of the present invention is the search for new compounds in the series of derivatives-glycyrrhizic acid (GL), which has anti-AIDS activity.

This goal is achieved glycopeptide-GK formula (I) exhibiting anti-AIDS activity.

Antiviral activity presents the compound (I) was studied on the model of primary HIV-1-infected lymphoid cells MT-4. Solution of the drug in DMSO ml, DMSO to a final concentration of 0.5-2.0%. In preliminary experiments it was found that DMSO at concentrations of 0.5-2.0% does not block the reproduction of HIV-1. About the inhibition of reproduction of HIV-1 in cells judged to reduce the activity of the reverse transcriptase and reduced accumulation of viral antigen (enzyme-linked immunosorbent assay) and cultural liquid on the 4th day of cultivation compared with the control (without addition of drug).

As reference drugs used one of the most effective for the treatment of AIDS funds - azidothymidine, the mechanism of action is associated with blocking reverse transcriptase and armirovanie of viral DNA synthesis (5) and glycyrrhizinic acid effectively inhibitory reproduction of HIV-1 in cells in vitro. The main disadvantage of AZT is its high toxicity (6).

The table shows the results of the experiments. It is established that the compound (I) inhibits the reproduction of HIV-1 in cell culture MG-4 at concentrations from 0.25 to 1.0 mg/ml the level of antiviral activity glikopeptid (I) is not inferior to AZT and compare it with the General Ledger. Glikopeptid (I) does not affect the cell culture toxic effect, in contrast to AZT. Moreover, if the. ) (7-10 times higher than in the case of AZT and 3-4 times higher than in the case of the civil code).

LD50glycopeptide (I) = 2000 (1666-2400) mg/kg (intraperitoneally) (mouse). This compound belongs to the class IV hazardous substance.

Synthesis of glycopeptide (I) was performed by the method of activated (N-hydroxysuccinimide) esters without prior protection of the hydroxyl groups of the carbohydrate chains of the molecules of the glycoside. The output of glycopeptide (I) 76,0%. Analytically pure product was obtained through column chromatography on silica gel by elution with a mixture of solvents chloroform-methanol = 50 : 1 and 25 : 1 (v/v) with an output of 60%.

Thus, the new low-toxic derivative-glycyrrhizic acid - glikopeptid (I) effectively inhibits HIV-1 in vitro (in culture cells (MT-4), is less toxic than AZT, not inferior to the activity of the latter and comparable effectiveness with-Ledger.

P R I m e R 1. The study of anti-AIDS activity.

Antiviral activity of glycopeptide (I) was studied on the model of primary HIV-1-infected lymphoid cells MT-4 in vitro. Solutions of drugs in DMSO (20-50 mg/kg) were introduced into a suspension of HIV-1-infected cells to a final concentration of 0.5-2.0%. In preliminary experiments it was found, almost to reduce the activity of the reverse transcriptase and reduced accumulation of viral antigen (enzyme-linked immunosorbent assay) in the culture fluid 4 days of culture compared with the control (without addition of drug). Were used for comparison one of the most effective for the treatment of AIDS drugs - azidothymidine (AZT) and-glycyrrhizinic acid (GK), effectively inhibitory reproduction of HIV-1 in cells in vitro. The results of the experiments are given in the table.

As can be seen from the table, glikopeptid (I) effectively inhibits the reproduction of HIV-1 in cell cultures at the indicated concentrations (95,3-97,3% ). The level of antiviral activity of compound (I) is not inferior to AZT and comparable to the General Ledger. The proposed derivative-Ledger does not have a culture of cells of toxic effects in contrast to AZT. The number of living cells in culture handling glycopeptides increases compared with the control (without addition of drug).

P R I m m e R 2. Getting glycopeptide (I).

Getting hydrochloride dimethyl ester of L-aspartic acid.

To a suspension of 10 g (75 mmol) of L-aspartic acid in 200 ml of methanol while cooling in an ice bath was added dropwise 10 ml of distilled chloride tonila, stirred at 0-5aboutWith 1.5 h until complete dissolution of the precipitate, incubated at room temperature for 12 hours by Evaporation of the solvent in vacuum at 40aboutTo obtain 14.2 g (96%) syrupy L East the product of 11.8 g (80%), so pl. 115-116aboutC. lit. so pl. 116-117about[7].

Synthesis of glycopeptide (I).

To a solution of 1.64 g (2 mmol) of purified-glycyrrhizic acid (92-95% ) in 50 ml of dry dioxane at 0aboutadd 1.2 g (10.4 mmol) of N-hydroxysuccinimide and 1.3 g (6 mmol) N,N'-dicyclohexylcarbodiimide and stirred at this temperature for 2.5-3 h at room 6-7 hours, leave the mixture overnight at 4-8aboutC, the precipitation is filtered off dicyclohexylamine, to the filtrate after cooling in a bath of ice was added 1.7 g L-Asp(OMe)2HCl (7 mmol) and dropwise to 1.4 ml (13.7 mmol) of distilled triethylamine and incubated the mixture at room temperature with occasional stirring for 24 hours the Solvent is evaporated in vacuum, the residue is dissolved in methylene chloride (200 ml), washed with 5% Hcl, water, 5% NaHCO3, water and dried over MgSO4. By evaporation of the solvent in vacuo gain of 1.9 g (76%) glycopeptide (I), which chromatographic on a column of silica gel L (100/250 , Czechoslovak), elwira mixture of chloroform-methanol 50 : 1, 25 : 1 and 10 : 1 (v/v). A mixture of 50 : 1 and 25 : 1 wash 1.5 g (60%) of analytically pure product (I) in the form of amorphous material, yellow, Rf = 0.50 in (chloroform-methanol-water= 45 : 10 : 1), [ ]D20= =+60o(=0,02; methanol).

Found, %: C 56,98; H 7,07; N 3,23.

C60H89N3O25.

Calculated, %: C 57,54, H 7,16; N 3,35.

Soluble in methanol, ethanol, acetone, tetrahydrofuran, dioxane, DMF.

Glikopeptid - glycyrrhizic acid dimethyl ester, L-aspartic acid of General formula

< / BR>
where R is - L - Asp (OMe)2, OH,

exhibiting anti-AIDS activity.

 

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